Journal
DEVELOPMENTAL CELL
Volume 21, Issue 4, Pages 627-641Publisher
CELL PRESS
DOI: 10.1016/j.devcel.2011.08.005
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Funding
- Marie Curie Fellowship [OIF-CT-2005-022003]
- MRC UK [G0901539]
- Royal Society
- King's College London
- March of Dimes and Birth Defects Foundation [6-FY03-071]
- National Institutes of Health [RO1 HD43997, 2RO1 HD061403, R21 DE18031]
- Cleft Palate Foundation
- Alice Bohmfalk Trust
- MRC [G0901539] Funding Source: UKRI
- Medical Research Council [G0901539] Funding Source: researchfish
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Morphogenesis of mammalian facial processes requires coordination of cellular proliferation, migration, and apoptosis to develop intricate features. Cleft lip and/or palate (CUP), the most frequent human craniofacial birth defect, can be caused by perturbation of any of these programs. Mutations of WNT, P63, and IRF6 yield CUP in humans and mice; however, how these genes are regulated remains elusive. We generated mouse lines lacking Pbx genes in cephalic ectoderm and demonstrated that they exhibit fully penetrant CUP and perturbed Wnt signaling. We also characterized a midfacial regulatory element that Pbx proteins bind to control the expression of Wnt9b-Wnt3, which in turn regulates p63. Altogether, we establish a Pbx-dependent Wnt-p63-Irf6 regulatory module in midfacial ectoderm that is conserved within mammals. Dysregulation of this network leads to localized suppression of midfacial apoptosis and CUP. Ectopic Wnt ectodermal expression in Pbx mutants rescues the clefting, opening avenues for tissue repair.
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